HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

High-affinity Rb binding, p53 inhibition, subcellular localization, and transformation by wild-type or tumor-derived shortened Merkel cell polyomavirus large T antigens.

AbstractUNLABELLED:
Interference with tumor suppressor pathways by polyomavirus-encoded tumor antigens (T-Ags) can result in transformation. Consequently, it is thought that T-Ags encoded by Merkel cell polyomavirus (MCPyV), a virus integrated in ∼90% of all Merkel cell carcinoma (MCC) cases, are major contributors to tumorigenesis. The MCPyV large T-Ag (LT-Ag) has preserved the key functional domains present in all family members but has also acquired unique regions that flank the LxCxE motif. As these regions may mediate unique functions, or may modulate those shared with T-Ags of other polyomaviruses, functional studies of MCPyV T-Ags are required. Here, we have performed a comparative study of full-length or MCC-derived truncated LT-Ags with regard to their biochemical characteristics, their ability to bind to retinoblastoma (Rb) and p53 proteins, and their transforming potential. We provide evidence that full-length MCPyV LT-Ag may not directly bind to p53 but nevertheless can significantly reduce p53-dependent transcription in reporter assays. Although early region expression constructs harboring either full-length or MCC-derived truncated LT-Ag genes can transform primary baby rat kidney cells, truncated LT-Ags do not bind to p53 or reduce p53-dependent transcription. Interestingly, shortened LT-Ags exhibit a very high binding affinity for Rb, as shown by coimmunoprecipitation and in vitro binding studies. Additionally, we show that truncated MCPyV LT-Ag proteins are expressed at higher levels than those for the wild-type protein and are able to partially relocalize Rb to the cytoplasm, indicating that truncated LT proteins may have gained additional features that distinguish them from the full-length protein.
IMPORTANCE:
MCPyV is one of the 12 known polyomaviruses that naturally infect humans. Among these, it is of particular interest since it is the only human polyomavirus known to be involved in tumorigenesis. MCPyV is thought to be causally linked to MCC, a rare skin tumor. In these tumors, viral DNA is monoclonally integrated into the genome of the tumor cells in up to 90% of all MCC cases, and the integrated MCV genomes, furthermore, harbor signature mutations in the so-called early region that selectively abrogate viral replication while preserving cell cycle deregulating functions of the virus. This study describes comparative studies of early region T-Ag protein characteristics, their ability to bind to Rb and p53, and their transforming potential.
AuthorsSophie Borchert, Manja Czech-Sioli, Friederike Neumann, Claudia Schmidt, Peter Wimmer, Thomas Dobner, Adam Grundhoff, Nicole Fischer
JournalJournal of virology (J Virol) Vol. 88 Issue 6 Pg. 3144-60 (Mar 2014) ISSN: 1098-5514 [Electronic] United States
PMID24371076 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, Viral, Tumor
  • Retinoblastoma Protein
  • TP53 protein, human
  • Tumor Suppressor Protein p53
Topics
  • Amino Acid Motifs
  • Animals
  • Antigens, Viral, Tumor (chemistry, genetics, metabolism)
  • Carcinoma, Merkel Cell (genetics, metabolism, pathology, virology)
  • Cell Line, Tumor
  • Cell Transformation, Viral
  • Down-Regulation
  • Humans
  • Kinetics
  • Merkel cell polyomavirus (chemistry, genetics, metabolism)
  • Polyomavirus Infections (genetics, metabolism, pathology, virology)
  • Protein Binding
  • Protein Transport
  • Rats
  • Rats, Sprague-Dawley
  • Retinoblastoma Protein (chemistry, genetics, metabolism)
  • Tumor Suppressor Protein p53 (chemistry, genetics, metabolism)
  • Tumor Virus Infections (genetics, metabolism, pathology, virology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: